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Preclinical research also shows that stress exposure enhances drug self\u2010administration and reinstates drug seeking in drug\u2010experienced animals. The deleterious effects of early life stress, child maltreatment, and accumulated adversity on alterations in the corticotropin releasing factor and hypothalamic\u2010pituitary\u2010adrenal axis (CRF\/HPA), the extrahypothalamic CRF, the autonomic arousal, and the central noradrenergic systems are also presented. The effects of these alterations on the corticostriatal\u2010limbic motivational, learning, and adaptation systems that include mesolimbic dopamine, glutamate, and gamma\u2010amino\u2010butyric acid (GABA) pathways are discussed as the underlying pathophysiology associated with stress\u2010related risk of addiction. The effects of regular and chronic drug use on alterations in these stress and motivational systems are also reviewed, with specific attention to the impact of these adaptations on stress regulation, impulse control, and perpetuation of compulsive drug seeking and relapse susceptibility. Finally, research gaps in furthering our understanding of the association between stress and addiction are presented, with the hope that addressing these unanswered questions will significantly influence new prevention and treatment strategies to address vulnerability to addiction.<\/jats:p>","DOI":"10.1196\/annals.1441.030","type":"journal-article","created":{"date-parts":[[2009,8,11]],"date-time":"2009-08-11T08:00:36Z","timestamp":1249977636000},"page":"105-130","source":"Crossref","is-referenced-by-count":1572,"title":["Chronic Stress, Drug Use, and Vulnerability to Addiction"],"prefix":"10.1196","volume":"1141","author":[{"given":"Rajita","family":"Sinha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,10,23]]},"reference":[{"key":"e_1_2_8_2_2","volume-title":"Stress and Emotion: A New Synthesis","author":"Lazarus 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